Description The proposed research reflects the interest of the Principal Investigator, John A. Porco, Jr., and his group in new chemical reaction development and the synthesis of biorelevant molecules using approaches inspired by the biogenesis of complex natural products. Their goal is to develop synthetic methodologies for a number of important natural product target classes, including the azaphilones, the rocaglamides and related compounds from the plant genus Aglaia, and the ansamycin tetrapetalone A. New reaction methodologies developed to accomplish the project aims include cycloisomerization routes to the azaphilones, photochemical dipolar cycloaddition to prepare the rocaglamides and related antitumor compounds, and transannular oxidative cyclization approaches to the ansamycin tetrapetalone A and congeners. In collaboration with Professor Guilford Jones' laboratory (Boston University), they will conduct photophysical studies to elucidate the mechanisms of novel photochemical transformations. They will evaluate the biological activity of synthetic compounds in specific biological collaborations with investigators from the National Cancer Institute (NCI), Cerylid Biosciences, and McGill University. In addition to methodology development, the synthesis of structurally complex and biologically active natural products and analogues will be pursued. The aims of the proposed project are to: [unreadable] Develop approaches to the asymmetric synthesis of the azaphilone class of natural products, and apply the methodologies towards the synthesis of the telomerase inhibitor diazaphilonic acid, the p53/MDM2 inhibitor chlorofusin, and the fatty acid synthase inhibitor CT2108A. [unreadable] Synthesize the rocaglamides and related compounds from Aglaia, including the antitumor agent aglaiastatin and the recently isolated, potent cytotoxic agent silvestrol. [unreadable] Pursue a biomimetic approach to the aglycone of the ansamycin tetrapetalone A based on a unique [4+3] transannular oxidative cyclization of an amido-hydroquinone and diene. Relevance to Public Health: The relevance to public health of the planned biomimetic syntheses of complex natural products entails identification of novel, biologically active agents. Such agents should play a key role in drug discovery related to various pathologies, including a variety of human cancers.